Bromantane

Bromantane, N-(4-bromophenyl)adamantan-2-amine, is a synthetic adamantane derivative. It came out of a Russian program that synthesized 329 adamantane derivatives and screened them for effects on animals' resistance to extreme conditions such as overheating and low oxygen (Morozov et al., 1999). A review names it and bemitil as the main actoprotectors, synthetic compounds studied for raising resistance to physical load without raising oxygen use (Oliynyk and Oh, 2012). Other names are bromantan, bromontan and Ladasten, and it is sometimes misspelled bromantine or bromatine.

A 2001 paper described it as widely used in Russia as a performance agent for athletes and as an immunostimulant (Iezhitsa et al., 2001).

Most of the literature is in Russian and comes from rodent and cell studies, plus a smaller set of Russian clinical studies.

Published work on bromantane falls into six areas, each summarized with its model. Apart from the clinical studies in the last area, the evidence comes from animals and animal tissue.

Physical work capacity

In mice and rats tested by swimming and treadmill running, 0.5 to 50 mg/kg raised work capacity. The effect exceeded that of phenamine (amphetamine) at optimal amounts by 1.3 to 1.6 times and lasted at least 24 hours. Bromantane also delayed the fall in performance and sped recovery during repeated exhausting runs, and in rats it prevented electron-microscopic changes in heart and skeletal muscle mitochondria (Morozov and Kleimenova, 1998). Models: mice and rats.

Dopamine synthesis and uptake

In rat brain preparations, bromantane had no direct effect on dopamine D1 to D3 or serotonin 5-HT1A and 5-HT2A receptors. A single intraperitoneal 50 mg/kg exposure raised striatal dopamine synthesis and release ex vivo. Bromantane also inhibited dopamine uptake into striatal synaptosomes (IC50 3.56 micromolar) but not serotonin uptake (Zimin et al., 2010). Another rat study at 50 mg/kg found higher expression of the genes for tyrosine hydroxylase and DOPA decarboxylase, the enzymes that make dopamine (Vakhitova et al., 2004). Models: rats and rat brain tissue.

Gene expression and synaptic plasticity

A single 50 mg/kg exposure by mouth changed tyrosine hydroxylase, dopamine and L-DOPA levels differently across five rat brain regions. In hippocampal preparations, 10 micromolar bromantane turned short-term potentiation of synaptic transmission into a long-lasting form; the protein synthesis inhibitor anisomycin blocked this and the D1/D5 antagonist SCH23390 reduced it (Mikhaylova et al., 2007). Models: rats and rat hippocampal tissue.

Anxiety-like behavior and inflammation

In BALB/c mice, 40 to 50 mg/kg by mouth prevented freezing and reduced defecation in the open field and activated behavior in the elevated plus maze, which the authors read as an anxiolytic effect (Seredenin et al., 1999). In male C57BL/6 mice given bacterial lipopolysaccharide to induce a depression-like state, five prior exposures at 30 or 50 mg/kg lowered plasma TNF-α and IL-6 and prevented behavior changes more potently than imipramine (Tallerova et al., 2011). Models: inbred mice.

Toxicology and offspring

Under Irwin's multi-test observation protocol in rats, single exposures of 30 to 300 mg/kg stimulated behavior and 600 to 9,600 mg/kg suppressed it, with pupil dilation at every amount tested (Iezhitsa et al., 2002). With long-term exposure, 150 and 600 mg/kg first raised and then lowered red cells, hemoglobin and white cells, with reversible agranulocytosis, plus enlarged liver cells and iron deposits in the spleen (Bugaeva et al., 1999).

When female rats received 30, 150 or 600 mg/kg by mouth for 16 days before mating, litter size fell by about 35 and 44 percent at 30 and 600 mg/kg and rose by about 45 percent at 150 mg/kg. In that group, 40 percent of pups were lost over three months, against 20 percent of controls (Iezhitsa et al., 2001). Models: rats.

Clinical studies of Ladasten in Russia

These Russian-language studies are research history. Asthenia means persistent fatigue and weakness. In 10 healthy volunteers, a single exposure produced EEG signs of a moderate rise in vigilance without changing subjective state or main task measures, compared with placebo (Viatleva et al., 2000).

A randomized, blinded study in people with neurasthenia compared 28 days of Ladasten with placebo and reported faster and larger symptom reductions with Ladasten and no withdrawal syndrome after stopping (Neznamov et al., 2009). A 28-center study of 728 people with asthenic disorders reported 76.0 and 90.8 percent responders on two clinical global impression scales after 28 days of Ladasten; its abstract describes no comparison group (Voznesenskaia et al., 2010). Model: human studies in Russia.